The present invention is directed to ornithine and arginine salts of keto analogs of branched chain essential amino acids, and the use of these salts particularly in the treatment of hyperammonemia.
Various hepatic disorders are characterized by hyperammonemia and portal systemic encephalopathy. The conditions are manifested clinically after ingestion of proteins by vomiting, agitation, lethargy and impaired mental and physical processes. Prior art treatment of these conditions has generally been based upon attempts to reduce the production of ammonia in the intestines and to restrict dietary protein.
Ornithine and arginine have long been known to provide protection against the toxic effects of ammonia salts. See Greenstein et al. Archives Of Biochemistry And Biophysics 64:342 (1956); Gullino et al. Archives Of Biochemistry And Biophysics 64:319 (1956); Najarian and Harper, Proceedings Of The Society Of Experimental Biology And Medicine 92:560 (1956); Salvatore et al., Archives Of Biochemistry And Biophysics 107:499 (1964); Roberge and Charbonneau, Life Sciences 8:369 (1969). Attempts have been made to use these compounds therapeutically in hyperammonemic patients. See Fahey, American Journal Of Medicine 22:860 (1957); Cachin, La Presse Medicale 69:1473 (1961); and Michel, La Presse Medicale 79:867 (1971). However, provision of ornithine or arginine per se is limited in such patients because of their decreased tolerance for nitrogen.
Individuals suffering from hyperammonemia and portal systemic encephalopathy are commonly deficient in protein owing to their intolerance of dietary protein. Therefore, nitrogen-free analogs of essential amino acids have also been used therapeutically in hyperammonemic subjects for the reduction of ammonia in the bloodstream while simultaneously promoting protein synthesis. My U.S. Pat. Nos. 4,100,293 and 4,100,160 issued July 11, 1978 disclose the use of mixtures of keto and/or hydroxy analogs of essential amino acids in the treatment of hepatic disorders. See also Maddrey et al., Gastroenterology 71:190 (1976); Batshaw et al., New England Journal Of Medicine 292:1085 (1975); and Batshaw et al., Pediatrics 58:227 (1976). However, the nitrogen-free analogs of essential amino acids are somewhat unpleasant tasting and have limited solubility as Ca salts.